1. Field of the Invention
The present invention relates to a novel synthetic route for preparing .alpha.-arylpropionic acids, e.g., 2-(6'-methoxy-2'-naphthyl)propionic acid (naproxen) and 2-(p-isobutylphenyl)propionic acid (ibuprofen), and to intermediates prepared and utilized in such synthetic route.
2. Prior Art
Naproxen is a nonsteroidal compound having anti-inflammatory, nonnarcotic analgesic and antipyretic activities. It belongs to a group of compounds, generally classified as arylpropionic acids or arylalkanoic acids, which group includes naproxen, ibuprofen, ketoprofen, fenoprofen, suprofen, flurbiprofen, benoxaprofen, pirprofen and carprofen. Each of the compounds of this group are related in that they are propionic acid derivatives.
Many synthetic routes for producing arylpropionic acids and, in particular, naproxen have been proposed. The first synthetic routes produced a mixture of optical isomers or enantiomorphs. Thus, such routes required resolution of the mixture to obtain the more active isomer, such as with cinchonidine or glucamine. These resolution procedures, however, require numerous recrystallizations and are, therefore, not commercially attractive.
More recently, attempts have been made for preparing the pharmaceutically useful optical isomer in excess of the physiologically inactive isomer so that the resolution procedure could be simplified. For example, U.S. Pat. No. 4,542,237 discloses a process for preparing .alpha.-arylpropionic acids and, in particular, a process for preparing naproxen, which involves a noncatalytic rearrangement of a ketal or thioketal of 2-hydroxy-1-(6'-methoxy-2'-naphthyl)propan-1-one by activating the .alpha.-hydroxy moiety with an esterifying agent to form the corresponding alkyl aryl ketal or thioketal ester substrate. Concomitant or sequential hydrolysis of the ester produces the corresponding arylpropionic acid, 2-(6'-methoxy-2'naphthyl)propionic acid. See also Piccolo et al, J. Org. Chem. 52, 10-14 (1987), and references cited therein. In the majority of cases, however, production of the desired isomer in enantiomeric excess has been limited and numerous recrystallizations are still required.
Asymmetric hydrogenation of arylpropenoic acids has been previously proposed as a method of further increasing the enantiomeric excess of the desired isomer. However, these procedures have had limited success in producing the desired optical isomer in enantiomeric excess sufficient to significantly simplify the resolution procedures. For example, Campolmi et al, U.S. Pat. No. 4,239,914 discloses catalytic asymmetric hydrogenation of 2-(6'-methoxy-2'-naphthyl)propenoic acid utilizing a chiral bidentate phosphine complex. Preferred compounds include 1,2-ethanediylbis(o-methoxyphenyl)phenylphosphine (DIPAMP), [2,3-0-isopropylidene-2, 3-dihydroxy-1,4-bis(diphenylphosphine)butane] (DIOP) and N,N'-bis-((+)-.about.-methylbenzyl)-N,N'-bis-(diphenylphosphine)ethylenedi amine (PNNP). The catalytic asymmetric hydrogenations are conducted with a DIOP catalyst at a temperature of 25.degree. C. and at H.sub.2 pressures of and 3.5 atmospheres (.about.15 p.s.i. and .about.52 p.s.i., respectively) and at 50.degree. C. and 3.5 atmospheres. Such a hydrogenation is also conducted with a PNNP catalyst at 0.degree. C. and 1 atm. Enantiomeric excess (e.e.) of the desired product is reported to be about 70% or less.
Although Campolmi et al disclose that the hydrogenation can be conducted at temperatures of between 0.degree. C. and 70.degree. C. and at pressures of between 1 and 50 atmospheres, it is reported in Asymmetric Catalysis, NATO ASI Series, Series E: Applied Sciences, pp. 24-26, B. Bosnich Editor, Martinus Nijhoff Publishers (1986) that in general catalytic asymmetric hydrogenations conducted at temperatures of less than about 25.degree. C. and/or at pressures greater than about 15 psig H.sub.2 result in decreased e.e.'s. See also Asymmetric Synthesis, Vol. 5--"Chiral Catalyst", pp. 60-62, J. D. Morrison, Editor, Academic Press, Inc. (1985).
It has now been discovered, contrary to the above teachings, that conducting asymmetric catalytic hydrogenations at temperatures below about 15.degree. C. and, optionally, at H.sub.2 pressures greater than about 5 atmospheres, (.about.75 psig) results in higher e.e.'s of the desired product such that resolution of the resulting optical isomer mixture is significantly simplified. It has also been discovered that higher e.e.'s can be obtained by conducting such hydrogenations at temperatures of up to about 30.degree. C. in the presence of an organic base or utilizing a specific asymmetric hydrogenation catalyst.
For example, Noyori et al, J. Org. Chem. 52, 3174-76 (1987), disclose asymmetric hydrogenation of 2-(6'-methoxy-2'-naphthyl)propenoic acid with a catalytic amount of Ru[(S)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl](CH.sub.3 CO.sub.2).sub.2 at about 2000 psig H.sub.2 and apparently, although not clearly, at 15.degree.-30.degree. C. to afford naproxen. However, it has now been discovered that utilizing this same catalyst at temperatures below about 15.degree. C. and, optionally, at high H.sub.2 pressures, significantly increases the enantiomeric excess of the desired isomer Furthermore, conducting the reaction in the presence of an organic base, even at temperatures up to about 30.degree. C., significantly increases the enantiomeric excess of the desired isomer.